Method for producing calcium phosphate powder

ABSTRACT

The present invention provides a method of manufacturing calcium phosphate powder comprising the steps of preparing a mixed material by mixing calcium hydroxide (Ca(OH) 2 ) powder and calcium hydrogenphosphate powder so that a molar ratio (Ca/P) of calcium to phosphor is set to a range of 1.45-1.72; conducting a mixing/milling treatment to the mixed material to cause a soft-mechanochemical compositing reaction thereby to prepare a calcium phosphate precursor; and conducting a heat treatment to thus obtained precursor at a temperature of 600° C. or more thereby to prepare calcium phosphate powder. According to the present invention, the manufacturing process is simple and the manufacturing cost can be remarkably reduced. In addition, fine calcium phosphate powder excellent in characteristics can be easily manufactured in a short time.

TECHNICAL FIELD

The present invention relates to a method of manufacturing calciumphosphate powders such as β-tricalcium phosphate and hydroxy calciumphosphate or the like that are suitable for biomaterials, and moreparticularly relates to a method of manufacturing the calcium phosphatepowders that are capable of easily manufacturing the calcium phosphatepowders having an excellent characteristics through a simplemanufacturing process, and capable of greatly reducing a manufacturingcost of the calcium phosphates.

BACKGROUND ART

Calcium phosphates typically represented by β-tricalcium phosphate[Ca₃(PO₄)₂] and hydroxy calcium phosphate (hydroxy apatite)[Ca₁₀(PO₄)₆(OH)₂] are excellent in suitability to organism structure andhave an affinity to organism body, so that calcium phosphates arevaluable as bio-ceramic raw materials for constituting artificial bone,artificial tooth, artificial articulate or the like. In addition,calcium phosphates have been widely utilized as materials such as basematerial for tooth paste, additive for medical product, food additives,material for cosmetic chemist, separating/absorbing material forbiopolymer and material for constituting humidity sensor or the like.

Conventionally, these calcium phosphate powders have been manufacturedin accordance with the following methods such as wet-way (liquid phase)synthesizing method, dry-way (solid phase) synthesizing method,mechanochemical-reaction synthesizing method or the like. The wet-typesynthesizing method is a synthesizing methodin which a calcium solutionof calcium nitrate or the like is reacted with a phosphoric acidsolution of ammonium hydrogen phosphate, or an amorphous calciumphosphate is produced from a reaction being taken place in heterogeneoussystem comprising calcium hydroxide and phosphoric acid, then the formedamorphous calcium phosphate is subjected to a calcining treatmentthereby to produce β-tricalcium phosphate (β-TCP).

On the other hand, the dry-type synthesizing method is a method in whichcalcium carbonate is reacted with calcium pyrophosphate in a solid phaseat a high temperature thereby to obtain calcium phosphate powder.

On the other hand, in these years, there has been also proposed amanufacturing method comprising simple manufacturing process andutilizing the mechanochemical reaction as a new method of synthesizingthe calcium phosphate compound. For example, a publication of examinedJapanese Patent Application No. HEI3-69844 and a publication ofunexamined Japanese Patent Application No. HEI4-321508 disclose a methodin which calcium carbonate powder and calcium hydrogenphosphate powderor dihydrate thereof are mixed to prepare a slurry of which molar ratio(Ca/P) of calcium to phosphor is controlled, then thus obtained slurryis milled by using a ball mill or a vibration mill or the like to causereaction, thereafter, the reaction product is dried and heat-treated ata high temperature thereby to manufacture crystallized β-tricalciumphosphate (β-TCP).

Further, a publication of unexamined Japanese Patent Application No.HEI4-321508 discloses a method in which β-tricalcium phosphate is heatedunder a condition of existing water and pressingly treated thereby tomanufacture hydroxy calcium phosphate (hydroxy apatite) powder. In thisconnection, in the conventional process of manufacturing the hydroxycalcium phosphate, a process directly using the mechanochemical reactionhas not been adopted.

However, in case of the conventional wet-type synthesizing method, thesynthesizing conditions such as the molar ratio of a raw material,treating speed, pH or the like are required to be strictly controlled.On the other hand, there is a difficulty in obtaining a product having acompositional high purity and uniformity. At any rate, for the purposeof obtaining a powder having a compositional high-purity and uniformity,there is posed a problem that the manufacturing cost would be greatlyincreased.

In contrast, in case of the conventional dry-type synthesizing method,the synthesized calcium phosphate powder has a coarse grain size, sothat the powder cannot be directly used as a bio-ceramics raw materialand a fine grinding or milling treatment is essentially required wherebythere is posed a problem that the manufacturing process becomescomplicate and troublesome.

On the other hand, in case of the conventional synthesizing methodutilizing the mechanochemical react ion, a long-term grinding processfor 1 day to 50 hours is essentially required for advancing thereaction, thereby to cause a problem that the production cost is greatlyincreased. In addition, in order to smoothly advance the reaction, asolid content of the slurry is required to be set to a lower level.Therefore, there are posed various problems such that an amount of heatenergy to be put into the subsequent drying process remarkablyincreases, a drying operation is required to perform for a long time. Inaddition, for the purpose of pulverizing or grinding the coarselyaggregated bodies caused by the drying operation, an additional grindingprocess is essentially required, so that there is posed a fatal problemsuch that a running cost for the manufacturing facilities and theproduction cost are greatly increased.

The present invention had been achieved to solve the aforementionedproblems and an object of the present invention is to provide a methodof manufacturing calcium phosphate powder, the method being capable ofeasily manufacturing fine calcium phosphate powder having excellentcharacteristics by a simple manufacturing process and capable of greatlyreducing the production cost of the powder.

DISCLOSURE OF THE INVENTION

In order to achieve the aforementioned object, the inventors of thepresent invention had prepared calcium phosphate powders under variousconditions by using various material powders, reacting synthesizingmethods and pulverizing devices (grinding machines). Then, through manyexperiments, the inventors had comparatively reviewed the influences ofthe differences in the manufacturing conditions onto characteristics andmanufacturing cost of calcium phosphate powder as a product.

As a result, the inventors had found and obtained the followingknowledge. That is, when calcium hydroxide powder as a raw material isused in place of the conventional calcium carbonate, then the calciumhydroxide powder is mixed to calcium hydrogen phosphate powder therebyto prepare a mixed material, then the mixed material is further mixedand milled to take place a mechanochemical reaction. Thereafter, whenthe reaction product is heat-treated, there can be obtained knowledgethat fine particles of calcium phosphate compound having a highcrystallinity and high homogeneity can be effectively manufactured in ashort time.

In particular, when a multi-ring media type ultrafine mill comprising anumber of ring-shaped milling media is used as a mixing and millingdevice for advancing a mechanochemical reaction by conducting the mixingand the milling of the mixed material, there could be also obtained thefindings such that a reaction activity of the mixed material wasincreased, and it became possible to rapidly advance the abovemechanochemical reaction whereby a production efficiency of the calciumphosphate compound could be remarkably increased.

Furthermore, in the conventional various synthesizing methods conductedin a wet, the solid component content (viscosity) of the mixed materialslurry required to be suppressed to a lower level, and the mixedmaterial slurry is required to be mixed and pulverized for a long time.In contrast, when the above ultrafine mill is used, even if the slurryhas a high solid content and a high viscosity, there could be alsoobtained a finding that it becomes possible to mix and pulverize theslurry in a short time whereby the production efficiency of the calciumphosphate compound could be remarkably increased.

The present invention had been achieved on the basis of the abovefindings. Namely, a method of manufacturing calcium phosphate powderaccording to the present invention comprises the steps of preparing amixed material by mixing calcium hydroxide (Ca((OH)₂) powder and calciumhydrogenphosphate powder so that a molar ratio (Ca/P) of calcium tophosphor is set to a range of 1.45-1.72; conducting a mixing/millingtreatment to the mixed material to cause a soft-mechanochemicalcompositing reaction thereby to prepare a calcium phosphate precursor;conducting a heat treatment to thus obtained precursor at a temperatureof 600° C. or more thereby to prepare a calcium phosphate powder.

In the above method, it is preferable that the calcium hydrogenphosphateis at least one compound selected from the group consisting of calciummonohydrogenphosphate (CaHPO₄), calcium monohydrogenphosphate dihydrate(CaHPO₄.2H₂O), calcium dihydrogenphosphate (Ca(H₂PO₄)₂); and calciumdihydrogenphosphate monohydrate (Ca(HPO₄)₂.H₂O).

Further, it is preferable that the calcium phosphate to be preparedafter the heat treatment is at least one of β-tricalcium phosphate (TCP)and calcium hydroxyphosphate (hydroxyapatite: HAp). Furthermore, it isalso preferable that the molar ratio (Ca/P) of calcium to phosphorcontained in the mixed material is set to a range of 1.45-1.55, thecalcium phosphate precursor to be formed by the soft-mechanochemicalcompositing reaction is tricalcium phosphate precursor, and the calciumphosphate to be prepared after the heat treatment is β-tricalciumphosphate.

In addition, it is also preferable that the molar ratio (Ca/P) ofcalcium to phosphor contained in the mixed material is set to a range of1.62-1.72, the calcium phosphate precursor to be formed by thesoft-mechanochemical compositing reaction is hydroxyapatite (HAp), andthe calcium phosphate to be prepared after the heat treatment is calciumhydroxyphosphate.

Further, the mixing/milling treatment for the mixed material may beperformed by a dry-process. Furthermore, the mixed material may beprepared in a form of slurry and the mixing/milling treatment for theslurry may be performed by a wet-process. In addition, it is preferablethat a content (concentration) of solid component contained in theslurry is set to 15-50 wt %. In particular, it is preferable that themixing/milling treatment for the mixed material is performed by means ofa multi-ring type ultrafine mill comprising a number of ring-shapedpulverizing media.

The present invention adopts a countermeasure in which calcium hydroxide(Ca(OH)₂) powder is used as a material in place of calcium carbonatethat has been conventionally used as the material, and calcium hydroxideand calcium hydrogenphosphate are mixed and milled so that an interreaction i.e. soft-mechanochemical reaction between acid-base points atsurface of material particles is taken place whereby the calciumphosphate powders such as β-tricalcium phosphate or the like issynthesized in a short time.

More concretely to say, the manufacturing method comprises the steps ofpreparing a mixed material by weighing and mixing calcium hydroxide(Ca(OH)₂) powder and calcium dihydrogenphosphate monohydrate powder orthe like so that a molar ratio (Ca/P) of calcium to phosphor is set to arange of 1.45-1.72; putting the mixed material into a vessel of amilling device, mixing and milling the mixed material underpredetermined milling conditions to form a precursor, and conducting aheat treatment to the obtained precursor at a temperature of 600° C. ormore thereby to synthesize fine calcium phosphate powders such asβ-tricalcium phosphate, calcium hydroxyphosphate or the like.

In the above method, as the material of the calcium hydrogenphosphate,it is preferable to use at least one compound selected from the groupconsisting of calcium monohydrogenphosphate (CaHPO₄), calciummonohydrogenphosphate dihydrate (CaHPO₄.2H₂O), calciumdihydrogenphosphate (Ca(H₂PO₄)₂) and calcium dihydrogenphosphatemonohydrate (Ca(H₂PO₄)₂.H₂O).

The above calcium hydroxide (Ca(OH)₂) powder and calciumhydrogenphosphate powder are mixed so that a molar ratio (Ca/P) ofcalcium to phosphor is set to a range of 1.45-1.72 thereby to preparethe mixed material. In particular, when a mixed material controlled tohave a molar ratio of 1.45-1.55 is mixed and milled so that themechanochemical compositing reaction takes place thereby to form aprecursor, then the precursor is subjected to a heat treatment at atemperature of 600° C. or more, β-tricalcium phosphate (Ca₃(PO₄)₂) (TCP)is efficiently formed in accordance with the following formulae of(1)-(4):

Ca(OH)₂+2CaHPO₄→Ca₃(PO₄) ₂+2H₂O  (1)

Ca(OH)₂+2CaHPO₄2.H₂O→Ca₃(PO₄)₂+6H₂O  (2)

2Ca(OH)₂+Ca(H₂PO₄)₂→Ca₃(PO₄)₂+4H₂O  (3)

2Ca(OH)₂+Ca(H₂PO₄)₂.H₂O→Ca₃(PO₄)₂+5H₂O  (4)

On the other hand, when a mixed material controlled to have a molarratio of 1.62-1.72 is mixed and milled so that the mechanochemicalcompositing reaction is take place thereby to form a precursor, then theprecursor is subjected to a heat treatment at a temperature of 600° C.or more, calcium hydroxyphosphate (Ca₁₀(PO₄)₆ (OH)₂: hydroxyapatite(HAp)) is efficiently formed in accordance with the following formulae(5)-(8):

4Ca(OH)₂+6CaHPO₄→Ca₁₀(PO₄)₆(OH)₂+4H₂O+H₂↑  (5)

4Ca(OH)₂+6CaHPO₄.2H₂O→Ca₁₀(PO₄)₆(OH)₂+16H₂O+H₂↑  (6)

7Ca(OH)₂+3Ca(H₂PO₄)₂→Ca₁₀(PO₄)₆(OH)₂+12H₂O  (7)

7Ca(OH)₂+3Ca(H₂PO₄)₂.H₂O→Ca₁₀(PO₄)₆(OH)₂+15H₂O  (8)

In addition, it is considered that when a predetermined amount ofcalcium oxide (CaO) is mixed to the above mixed material, it becomespossible to form tetracalcium phosphate (Ca₄(PO₄)₂.O:TTCP) in accordancewith the following formulae (9) and (10):

Ca(OH)₂+2CaHPO₄+CaO→Ca₄(PO₄)₂.O+2H₂O  (9)

2Ca(OH)₂+Ca(H₂PO₄)₂.H2O+CaO→Ca₄(PO₄)₂.O+5H₂O  (10)

In addition, it is considered that when a predetermined amount ofcalcium fluoride (CaF₂) is mixed to the above mixed material, it becomespossible to form fluorine apatite (Ca₁₀(PO₄)₆F₂) in accordance with thefollowing formulae (11) and (12):

3Ca(OH)₂+6CaHPO₄+CaF₂→Ca₁₀(PO₄)₆F₂+3H₂O  (11)

 6Ca(OH)₂+3Ca(H₂PO₄)₂.H₂O+CaF₂→Ca₁₀(PO₄)₆F₂+12H₂O  (12)

In the manufacturing method of this invention, when thesoft-mechanochemical reaction is advanced in the process of mixing andmilling the mixed material, the above various calcium phosphateprecursors are formed. The above mechanochemical compositing reactioncan be advanced as a solid phase reaction in a dry-process in which amaterial powder is mixed and milled without adding a dispersing mediumto the material powder. On the other hand, the compositing reaction canbe also advanced as a liquid phase reaction in a wet-process in which aslurry prepared by dispersing the mixed material powder in a solvent ismixed and milled.

As the milling device for promoting the soft-mechanochemical compositingreaction by mixing and pulverizing the above mixed material, amotor-driven mortar, a vibration mill and a planetary ball mill or thelike are considered to be adopted. However, in these milling devices, acentrifugal effect is relatively small, and mechanical stress andimpacting forces to be imparted to the material are insufficient.Therefore, even if the milling operation is carried out for about onehour or so, it is very difficult to impart sufficient reaction activityto the mixed material and also difficult to advance thesoft-mechanochemical reaction. For this reason, in general, the reactionactivity cannot be imparted to the mixed material powder until thematerial slurry is subjected to the treatment for a long time of about10-50 hours or more. Accordingly, the above milling devices are notconsidered to be effective for simplifying the manufacturing processes.

Therefore, in the manufacturing method of the present invention, it ispreferable to adopt various impacting-type grinding mills or a powdersurface modifying device capable of repeatedly imparting an impactingforce to the mixed material in a short time.

In the mixing and milling treatment for advancing the abovesoft-mechanochemical compositing reaction, the centrifugal effect (Z) tobe imparted to the mixed material powder is required to be at least 15.In this connection, the centrifugal effect (Z) is a quantitative indexshowing a magnitude of pulverizing force, and is a ratio of thecentrifugal force (Fc) to a gravitational force (Fg). The centrifugaleffect (Z) is expressed by the following formula:

Z=Fc/Fg=rω ² /g(−)

wherein r is radius of rotation, ω is angular speed, and g isgravitational acceleration.

When the centrifugal effect (Z) is less than 15, the impacting force tobe imparted to the mixed material is insufficient, and it becomesimpossible to increase the reaction activity by forming distortions incrystal structure of the surface portion of the material particles in ashort time. Therefore, in order to increase the reaction activity of themixed material and to prepare the mixed material having a uniformity, itis required to use a milling device capable of imparting impacting forcehaving a centrifugal effect (Z) of 15 or more, preferably 70 or more,and more preferably 150 or more.

In this connection, the method of the present invention therefore usessuch an ultrafine mill (multi-ring type pulverizing mill) as shown inFIGS. 1 and 2 as the milling device comprising a number of ring-shapedpulverizing media for rapidly carrying out the soft-mechanochemicalcompositing treatment. This ultrafine mill is capable of applying impactforce and friction to powder particles so as to enhance the reactionactivity thereof, and efficiently mixing and milling the powderparticles within a short time. The device comprises a cylindrical casing1, a main shaft 4 which is rotated in the casing 1, and a plurality ofsub-shafts 6 which are rotated around the main shaft 4 in linkage withthe rotation of the main shaft 4, wherein each of the sub-shafts 6 beingprovided with many ring members 9 as grinding media. Although the sizeof each of the ring members 9 as the grinding media depends upon thetype and size of the treatment device used, an outer diameter of themember is 25 to 45 mm, and the thickness of the member is several mm.Although the material for constituting the ring members 9 depends uponthe physical properties of a material to be processed, the ring members9 can be composed of stainless steel, ceramic materials such as alumina,zircoma or the like, or a hard carbide material such as WC.

The above casing 1 has an internal peripheral surface 2 having a centeraxis in a longitudinal direction, and comprises a rotational mechanism 3provided in the casing 1 serving as a processing chamber. The rotationalmechanism 3 comprises the main shaft 4 concentric with the casing 1, apair of press plates 5 and 5′ which are fixed at a predeterminedinterval therebetween in the longitudinal direction of the main shaft 4,and the sub-shafts 6 which are fixed by the press plates 5 and 5′ so asto be arranged at the same distance from the main shaft 4 in paralleltherewith.

Each of the press plates 5 and 5′ has a form in which the same number ofarms as the number of the sub-shafts 6 are radially projected. The formof the press plates 5 and 5′ in which the arms are provided at equalintervals, not a simple disk form, can improve the degree of convection(mixing) of a material to be processed, which is put into the casing 1,and decrease as much as possible the amount of the material to beprocessed, which is deposited as a dead stock on the upper press plate5.

Each of the sub-shafts 6 comprises a long bolt-like member having endsthat are respectively passed through holes provided at the ends of thearms of both press plates 5 and 5′ and tightened by nuts 7. The upperend of the main shaft 4 is connected directly to a driving Source suchas a motor (not shown) or provided with a pulley so that the rotationalforce of the driving source is transmitted to the main shaft 4 through aV belt.

As shown in FIG. 2, for the purpose of increasing wear resistance, theremay be a case where a cylindrical collar 8 is fitted on each of thesub-shafts 6 with a small gap therebetween, and a plurality of ringmembers 9 are retractably mounted on each of the collar 8. Each of thering members 9 has an internal diameter sufficiently larger than theouter diameter of the collar 8, and is constructed so as to have asufficient gap between the internal peripheral surface of the ringmember 9 and the external peripheral surface of the collar 8 when theexternal peripheral surface of the ring member 9 contacts the internalperipheral surface 2 of the casing 1.

The ring members 9 are stacked to form a gap corresponding to the totalthickness of 2 to 3 ring members 9 between the upper side of theuppermost ring member 9 and the lower side of the press plate 5, but notclosely stacked between both press plates 5 and 5′ without a gap. Thisstacking structure makes the ring members 9 rotatively around each ofthe collars 8.

Each of the ring members 9 is formed in a cylindrical form havingparallel upper and lower surfaces, which is a so-called washer-like formhaving smooth upper and lower surfaces, and an outer peripheral surface.If required, the outer peripheral surface may be curved for promotingbite into the powder material.

Agitating blades 10 and 10′ are radially disposed at upper and lowerportions of the main shaft 4, which are below the lower press plate 5′and above the upper press plate 5, respectively, so as to agitate thematerial to be processed, which is put into the casing 1.

To an upper flange 13 of the casing 1 is fixed an upper cover 11 havinga through hole by tightening members such as bolts and nuts, with apacking 12 therebetween. The main shaft 4 is passed through the throughhole of the upper cover 11, the through hole being provided with an oilseal 14 for sealing the main shaft 4, and an oil seal holder 15 forholding the oil seal 14. In order to prevent a temperature rise of thematerial to be processed during grinding, the side of the casing 1 has ajacket structure 16. A refrigerant supply port 17 and discharge port 18are provided in the jacket 16 so that the material to be processed whichis put into the casing 1 can be cooled by continuously supplying any oneof various refrigerants into the jacket 16.

In the grinding/milling device (ultrafine mill) constructed as describedabove, a gap of several millimeters (mm) is formed between the outerperiphery of each of the sub-shafts 6 and the inner peripheries of thering members 9 so that the ring members 9 can be freely independentlyrotated. The ring members 9 serving as the grinding media are radiallymoved by an amount corresponding to the gap due to the centrifugal forcegenerated by the rotation of the main shaft 4, and circumferentiallyrotated in the casing 1 while being pressed on the inner periphery 2 ofthe casing 1. At the same time, the ring members 9 themselves arerotated around the sub-shafts 6 due to the friction between the innerperipheral surface 2 and the ring members 9. Namely, the ring members 9are moved in the casing 1 while being repeatedly rotated around the mainshaft 4 and each of the sub-shafts 6.

When the raw material mixture powder in an amount corresponding to 10 to80% of the effective volumes of the grinding portion is put into thecasing 1 and then subjected to the soft-mechanochemical treatment byrotating the main shaft 4, the raw material mixture powder is heldbetween the rotating ring members 9 and the internal peripheral surface2 of the casing 1, and subjected to impact force (compressive force)corresponding to the centrifugal effect caused by the ring members 9 andthe grinding/milling function due to the rotation of the ring members 9themselves. As a result, the raw material mixture powder is ground anddispersed, and, at the same time, strains and distortions are producedin the crystal structure of the particle surfaces of the mixture powder,so that a soft-mechanochemical compositing reaction is rapidly advancedthereby to form a calcium phosphate precursor in which the reactivity ofthe surfaces of the raw material mixture powder is enhanced. Thecentrifugal effect Z exerted on the raw material mixture powder iscontrolled by changing the rotational speed of the main shaft 4.

According to knowledge of the inventors of this invention, it has beenconfirmed that the soft-mechanochemical compositing reaction to beadvanced by mixing and pulverizing the mixed material is greatlyinfluenced by operating conditions such as a kind or magnitude of themechanical stress, pulverizing mechanism of the milling device,atmosphere for the treatment or the like.

In place of the conventional milling devices such as motor-drivenmortar, various ball mills or the like, when there is particularly useda milling device like the above multi-ring media type ultrafine millhaving a special pulverizing mechanism provided with a number ofring-shaped pulverizing media, the reactivity of the material mixturecan be rapidly increased by the short-time mixing and pulverizingtreatment, so that it becomes possible to shorten a required time forthe soft-mechanochemical compositing reaction.

In the method of this invention when the mixing/milling operation isperformed and acid-base points are formed on surface of the materialparticles, the soft-mechanochemical reaction is advanced by a reactionmechanism in which new chemical bondings are directly formed by theinter-action between the acid-base points formed on the surfaces of thedifferent material particles, whereby the calcium phosphate precursor isformed. Although this reaction is one kind of a solid-phase reaction, ithas a characteristic of exhibiting a high reaction rate, so that a timerequired for synthesizing calcium phosphate compound can be greatlyshortened in comparison with that of the conventional method.

The reaction mechanism of the above soft-mechanochemical reactionmechanism to be used in the method of this invention is quite differentfrom that of the conventional mechanochemical reaction mainly consistingof a liquid-phase reaction disclosed in Japanese Patent Publication No.3 (1991)-69844 in which a dissolving of solid material is promoted by awet-type pulverization then a compositing reaction is advanced by amutual reaction of ions generated in a solution thereby to cause theliquid phase reaction.

That is, the method of this invention is a method wherein acidbasepoints are generated at the surface of the solid material particles byutilizing the mechanical stress and simultaneously cause the mutualreaction (inter-reaction). In this point, the reaction mechanism used inthis invention is also quite different from that of the conventionalsolid-phase method i.e., a high temperature solid-phase reacting methodin which the mutual reaction between the different material particles isadvanced by using heat energy thereby to form calcium phosphatecompound.

In particular, non-free water such as hydroxyl group and bound water(crystal water) is quite different from free water to be added to thematerial powder as dispersion medium in the conventional method. Thenon-free water has a strong function as a catalyser for promoting themechanochemical compositing reaction to be caused during the mixing andmilling the material mixture. Accordingly, when the calcium hydroxidepowder having the non-free water i.e., hydroxyl group or calciumhydrogenphosphate having the bound water is used as a starting materiallike this invention, the mechanochemical reaction can be rapidlyadvanced in the mixing/milling process thereby to effectively producecalcium phosphate precursor.

The catalytic action by the above non-free waters such as hydroxyl groupand the combined water or the like in the soft-mechanochemical reactionis similarly revealed in not only a case where the dry-typemixing/milling operation is performed without adding the non-free wateras the dispersing medium but also a case where the wet-typemixing/milling operation is performed to a highly-concentrated materialslurry which is prepared by adding the dispersion medium so as to have asolid content of 15-50 wt %, and more preferably to have a solid contentof 20-40 wt %.

In particular, when the material mixture to which the dispersion mediumsuch as water is not added is mixed and milled in a dry-process unlikethe conventional method, a drying-process is not required to perform tothe resulting precursor substance at a stage after the completion of thesoft-mechanochemical compositing reaction, so that the precursorsubstance can be immediately supplied to a heating-treatment process.Therefore, a crystallization of the precursor can be advanced by theheat treatment at a low temperature, so that calcium phosphate compoundssuch as β-tricalcium phosphate can be manufactured at high efficiencyand low cost.

When the precursor substance obtained by the above soft-mechanochemicalcompositing reaction is subjected to the heat treatment, calciumphosphate compounds such as β-tricalcium phosphate and hydroxy calciumphosphate can be manufactured. The above heat treatment is performed attemperature of 600-800° C. for 1-3 hours or at temperature of 900-950°C. for 1-10 minutes. Namely, in the heat treatment at 600+ C. or more,when the temperature is set to be low, the time required for the heattreatment is relatively lengthened. On the other hand, when thetemperature for the heat treatment is set to be lower than 600° C., apart of un-reacted material is left, so that the purity in substantialstructure and crystallizing property of the calcium phosphate compoundis lowered. When the above temperature and time for the heatingtreatment are controlled, it becomes possible to adjust and control thepurity in substantial structure and crystallinity of β-tricalciumphosphate and hydroxy calcium phosphate.

In the manufacturing method of this invention, for example, calciumhydroxide and calcium dihydrogenphosphate monohydrate powders are usedas starting materials so as to prepare a mixed powder of which molarratio of Ca to P is appropriately controlled and the mixed powder isfurther mixed and milled in dry-process, so that soft-mechanochemicalreaction is rapidly advanced thereby to form β-tricalcium phosphateprecursor. Then, when the precursor is subjected to a heat treatment attemperature of 600° C. or more, there can be manufactured finelycrystallized powder of β-tricalcium phosphate (TCP).

The above soft-mechanochemical reaction is caused even if the dispersingmedium such as water or the like is not existing and the reaction iscaused by an interaction between acid-base points existing on thesurfaces of different material particles. At this time, amechanochemical dehydrating reaction and an amorphousizing reaction areadvanced thereby to produce β-tricalcium phosphate precursor as anintermediate product.

The above mechanochemical dehydrating reaction is quite different froman ordinary heat-dehydrating reaction to be caused by heat energy andthe mechanochemical dehydrating reaction is a reaction in which abonding state of hydroxyl group is changed by the mechanical energycaused in the mixing/milling process. The change of the bonding state ofthe hydroxyl group takes an important role in forming β-tricalciumphosphate (TCP) precursor by the above soft-mechanochemical compositingreaction. A completion state (degree of advancement) of the abovevarious reactions, composition (purity) and molecular structure of theproduct or the like are totally evaluated by various analyzing andtesting methods such as thermogravimetry-differential thermal analysis(TG-DTA), X-ray diffraction method (XRD) and Fouier transform infraredmicroscope (FT-IR) or the like.

In the mixing/milling process in the method of this invention, achemical interaction is mainly taken place in addition to a merephysical mixing of different material particles. The material particlesize is changed by the milling operation thereby to increase surfaceenergy per unit volume of the material particles and to increase latticeinconsistencies such as dislocation of crystals and amorphousizing to becaused in a solid body of the material particles. Such increases of thesurface energy and the lattice inconsistency also become one factor forpromoting the aforementioned soft-mechanochemical compositing reaction.

In a case where the material mixture is treated under the conditions ofmixing/milling by dry-process in the method of this invention withoutadding a dispersion medium to the material mixture, a milled substance(precursor) to be obtained is dried powder, so that there is no need toadopt a drying process which had been deemed to be an essential processfor the synthesizing method based on the conventional wet-typemechanochemical reaction method. Therefore, when the precursor formed bythe reaction is directly subjected to the heat treatment, fine particlepowder of β-tricalcium phosphate crystal can be obtained while an inputamount of the heat energy is reduced. The production of β-tricalciumphosphate is due to the blended molar ratio of Ca to P, and hydroxycalcium phosphate can be also produced by changing the molar ratiothrough a similar process.

As mentioned above, the mixing/milling process in the method of thisinvention may be performed in accordance with the dry-type mixing methodin which the dispersing medium such as water is not added to thematerial mixture. However, the same effect can be also obtained inaccordance with a wet-type mixing method in which the dispersing mediumis added to the material mixture to prepare a material slurry having ahigh solid content of 15-50 wt %, preferably 20-45 wt %, then thematerial slurry is mixed/milled. In a case where this wet-type mixingmethod is adopted, the solid content of the material slurry can begreatly increased in comparison with that of the conventional method, itbecomes possible to efficiently manufacture calcium phosphate compoundsin a short time. In particular, when the aforementioned multi-ringmedium type ultrafine mill is used as the milling device for performingthe mixing/milling operation, the effective milling operation can beperformed with respect to the slurry having a high solid contents andhigh viscosity.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross sectional view showing a structure of a milling deviceused in the method of the present invention.

FIG. 2 is a cross sectional view taken along the line II—II of FIG. 1.

FIG. 3 is a graph showing an X ray diffraction (XRD) profile of aβ-tricalcium phosphate precursor obtained by the soft-mechanochemicalreaction caused at mixing/milling operation in Example 1 according tothe present invention.

FIG. 4 is a graph showing an X-ray diffraction profile of the materialmixture before the milling operation in Example 1.

FIG. 5 is a graph showing results of thermogravimetry-differentialthermal analysis (TG-DTA) of a β-tricalcium phosphate precursor obtainedby the soft-mechanochemical reaction caused in Example 1.

FIG. 6 is a graph showing an X-ray diffraction profile of a β-tricalciumphosphate (TCP) fine powder obtained by the heat treatment of theprecursor at a temperature of 930° C. for one minute performed inExample 1 according to the present invention.

FIG. 7 is a graph showing an X-ray diffraction profile of a precursorobtained by the soft-mechanochemical reaction caused at mixing/millingoperation in Example 4.

FIG. 8 is a graph showing TG-DTA profile of β-tricalcium phosphateprecursor obtained by the soft-mechanochemical reaction caused inExample 4 according to the present invention.

FIG. 9 is a graph showing a TG-DTA profile of the material mixturebefore the milling operation in Example 4.

FIG. 10 is a graph showing a variation of X-ray diffraction profile of aprecursor sample prepared at mixing/milling operation in Example 7.

FIG. 11 is a graph showing an X-ray diffraction profile of a hydroxycalcium phosphate precursor prepared in Example 8.

FIG. 12 is a graph showing an X-ray diffraction profile of a hydroxycalcium phosphate obtained by the heat treatment in Example 8.

FIG. 13 is a graph showing a variation of X-ray diffraction profile of asample prepared in Examples 9 as the time for the wet-typemixing/milling treatment had passed.

BEST MODE FOR EMBODYING THE INVENTION

Next, embodiments of the present invention will be explained on thebasis of the following Examples and Comparative Examples.

EXAMPLE 1

Calcium hydroxide powder (mfd. by Kanto Kagaku K.K., reagent grade 1)and calcium dihydrogenphosphate mono-hydrate (mfd. by Showa Kagaku K.K.,reagent grade 1) were weighed and blended so that a molar ratio (Ca/P)of calcium to phosphor was controlled to be 1.5, thereby to prepare amixed material.

50 g of this mixed material was put into a casing 1 of a multi-ringmedia type ultrafine mill (MICROS-O type mill, mfd. by K.K. Nara KikaiSeisakusho, technical specification: zirconia ring) shown in FIGS. 1 and2. Under a state where a cooling water having a temperature of 15° C.was circulated in a jacket 16 provided to an outer peripheral portion ofthe casing 1 thereby to keep the temperature of the casing 1 to be aconstant value, a rotation speed of the main shaft 4 was set to 800 rpmand mixing/milling operation for the mixed material slurry was carriedout for 60 minutes, so that the soft-mechanochemical compositingreaction was advanced thereby to prepare a precursor.

An X-ray diffraction (XRD) profile of thus milled sample i.e.,β-tricalcium phosphate precursor produced by the soft-mechanochemicalcompositing reaction caused at mixing/milling operation is shown in FIG.3. On the other hand, in order to compare with the state shown in FIG.3,an X-ray diffraction profile of the sample before the milling operationis shown in FIG. 4. The material mixture before the milling operationwas prepared in such a manner that calcium hydroxide powder and calciumdihydrogenphosphate mono-hydrate powder were weighed and blended so thata molar ratio (Ca/P) of Ca to P was controlled to be 1.5 thereby toprepare a mixture, then the mixture was sufficiently mixed and dispersedin acetone by means of a manual-mortar.

The thermogravimetry-differential thermo analysis measurement profile(TG-DTA graph) is shown in FIG. 5.

As shown in FIGS. 3 and 5, both calcium hydroxide powder and calciumdihydrogenphosphate mono-hydrate powder as starting materials were notdetected in the sample after the milling treatment, so that it wasconfirmed that the soft-mechanochemical compositing reaction wascompletely finished.

Further, 1 gram of the above milled sample was put into an electricfurnace (hyper-speed, high-temperature muffle furnace, SF-17L type: mfd.by Shibata Kagaku Kiki Kogyo K.K.), then heated at a heating speed of10° C./min. in air atmosphere and subjected to a heat treatment at 630°C. for two hours or at 930° C. for one minute. The heat-treated samplewas analyzed by X-ray diffraction method and thus obtained X-raydiffraction profile is shown in FIG. 6.

As is clear form FIG. 6, it was confirmed that each of the substancesproduced by the heat treatment was confirmed to be β-tricalciumphosphate crystal having a high degree of crystallization and astructural uniformity. In this connection, when the temperature of theheat treatment is set to be less than 600° C., the reaction wasincompletely advanced, so that it was found to be difficult to controlthe product qualities such as purity or the like.

Thus produced β-tricalcium phosphate powder was subjected to SEManalysis and grain size distribution analysis. As a result, β-tricalciumphosphate powder was found to be an aggregated body consisted ofultrafine particles each having an average grain size of about 1 μm.Further, when thus obtained β-tricalcium phosphate powder was subjectedto a heat treatment at a high temperature, for example at 1200° C. forabout one hour, it was confirmed that a β-tricalcium phosphate powderhaving a high degree of crystallization and structural uniformity couldbe also obtained.

Note, in all of Examples of the present invention and ComparativeExamples, X-ray diffraction analysis was conducted by using an MXPdevice (mfd. by Mac. Science K.K., scan speed: 5 deg/min, voltage: 40kv, current: 40 mA). Further, thermogravimetry-differential thermoanalysis (TG-DTA) was conducted by using a thermal analyzing system(001, TG-DTA2000 mfd. by Mac.Science K.K., standard sample Al₂O₃, N₂atmosphere). Furthermore, SEM analysis was conducted by using a scanningelectron microscope (S-530 type, mfd. by K.K. Hitachi Seisakusho). Inaddition, the grain size distribution analysis was conducted by using alaser diffraction type grain size distribution measuring device(SALD-2000A type, mfd. by K.K. Shimazu Seisakusho, water dispersant,ultrasonic dispersion, refractive index: 1.60-0.01i).

EXAMPLE 2

Calcium hydroxide powder (mfd. by Kanto Kagaku K.K., reagent grade 1)and calcium dihydrogenphosphate mono-hydrate (mfd. by Showa Kagaku K.K.)were weighed and blended so that a molar ratio (Ca/P) of Ca to P wascontrolled to be 1.55, thereby to prepare a mixed material.

50 g of this mixed material was mixed/milled under the same conditionsas in Example 1, so that the soft-mechanochemical compositing reactionwas advanced thereby to prepare a precursor. Thus obtained precursor wasthen subjected to the heat treatment under the same conditions as inExample 1, thereby to form calcium phosphate compound. Thus obtainedcalcium phosphate compound was analyzed by X-ray diffraction analyzingmethod. As a result, the compound was found to be β-tricalcium phosphatecrystal having a high degree of crystallization and structuraluniformity.

EXAMPLE 3

Calcium hydroxide powder (mfd. by Kanto Kagaku K.K., reagent grade 1)and calcium dihydrogenphosphate mono-hydrate (mfd. by Showa Kagaku K.K.)were weighed and blended so that a molar ratio (Ca/P) of Ca to P wascontrolled to be 1.45, thereby to prepare a mixed material.

50 g of this mixed material was mixed/milled under the same conditionsas in Example 1, so that the soft-mechanochemical compositing reactionwas advanced thereby to prepare a precursor. Thus obtained precursor wasthen subjected to the heat treatment under the same conditions as inExample 1, thereby to form calcium phosphate compound. Thus obtainedcalcium phosphate compound was analyzed by X-ray diffraction analyzingmethod. As a result, the compound was found to be β-tricalcium phosphatecrystal having a high degree of crystallization and structuraluniformity.

Purified water was added to each of the mixed/milled substances i.e.,β-tricalcium phosphate precursors obtained in the above Examples 1-3thereby to prepare slurries each having a solid content of 15 wt %,respectively. Each of the slurries was left as it was for one week undera normal temperature and pressure, thereafter, dried at a temperature of50° C. Thus obtained dried powder was analyzed by X-ray diffractionmethod. As a result, each of the precursors exhibited no change from astate before the purified water was added, so that it was confirmed thateach of the precursors had an excellent stability with respect to water.

Further, each of the precursors obtained in Examples 1-3 were left asthey were for three months in a state where the precursors contacted toatmosphere under normal temperature and pressure thereafter theresultant powders were analyzed by X-ray diffraction method As a result,each of the precursors exhibited no change from a state before theprecursors was left as it was, so that it was also confirmed that eachof the precursors had an excellent stability with respect to atmosphere.

Further, when the mixing/milling process is terminated in a state beforethe soft-mechanochemical compositing reaction is completely finished inthe above Examples 1-3, even if the milled sample is one in which asmall amount of calcium hydroxide powder and calcium dihydrogenphosphatemonohydrate powder as the starting materials is detected, β-tricalciumphosphate crystal particles having a high purity, high degree ofcrystallization and highly structural uniformity can be manufactured ifthe treating temperature in the subsequent heat treatment process issufficiently increased or the treating time is prolonged. Even in such acase, when the molar ratio (Ca/P) of Ca to P is outside the range of1.45-1.55, it becomes difficult to form β-tricalcium phosphate crystalparticles having a high degree of crystallization and highly structuraluniformity, thus being not preferable.

COMPARATIVE EXAMPLE 1

Calcium carbonate powder (mfd. by Kanto Kagaku K.K., reagent grade 1)and calcium dihydrogenphosphate mono-hydrate (mfd. by Showa Kagaku K.K.,reagent grade 1) were weighed and blended so that a molar ratio (Ca/P)of calcium to phosphor was controlled to be 1.5, thereby to prepare amixed material.

Purified water was added to the mixed material so that a solid contentwas controlled to be 25 wt % thereby to prepare a material slurry. 200 gof this material slurry was put into a casing 1 of a multi-ring mediatype ultrafine mill (MIC-O type mill. mfd. by K.K. Nara KikaiSeisakusho, technical specification: zirconia ring) shown in FIGS. 1 and2 Then, the material slurry was mixed/milled under the samemixing/milling conditions as in Example 1 except that the milling timewas set to 8 hours, so that the mechanochemical reaction was advancedthereby to prepare a milled powder.

Thus obtained milled powder was analyzed by X-ray diffraction method anddifferential thermal analysis. As a result, it was confirmed that alarge amount of non-reacted substance was remained in the milled powder.Therefore, in the manufacturing method of Comparative Example 1 based onthe conventional mechanochemical reaction, although the millingoperation was conducted for a long time of 8 hours, the advancing speedof the mechanochemical reaction was remarkably lowered in comparisonwith those of Examples 1-3.

COMPARATIVE EXAMPLE 2

Calcium carbonate powder (mfd. by Kanto Kagaku K.K., reagent grade 1)and calcium dihydrogenphosphate mono-hydrate (mfd. by Showa Kagaku K.K.,reagent grade 1) were weighed and blended so that a molar ratio (Ca/P)of calcium to phosphor was controlled to be 1.5, thereby to prepare amixed material.

Purified water was added to the mixed material so that a solid contentwas controlled to be 10 wt % thereby to prepare a material slurry. 200 gof this material slurry was put into a casing 1 of a multi-ring mediatype ultrafine mill (MIC-O type mill. mfd. by K.K. Nara KikaiSeisakusho, technical specification: zirconia ring) shown in FIGS. 1 and2. Then, the material slurry was mixed/milled under the samemixing/milling conditions as in Example 1 except that the milling timewas set to 8 hours, so that the mechanochemical reaction was advancedthereby to prepare a milled powder.

Thus obtained milled powder was analyzed by X-ray diffraction method anddifferential thermal analysis. As a result, it was confirmed that alarge amount of non-reacted substance was remained in the milled powder.Therefore, in the manufacturing method of Comparative Example 2 based onthe conventional mechanochemical reaction, although the millingoperation was conducted for a long time of 8 hours, the advancing speedof the mechanochemical reaction was remarkably lowered in comparisonwith those of Examples 1-3. Further, since the solid content of thematerial slurry was small, the manufacturing efficiency was found to bedisadvantageously lowered.

EXAMPLE 4

Calcium hydroxide powder (mfd. by Kanto Kagaku K.K., reagent grade 1)and calcium dihydrogenphosphate mono-hydrate (mfd. by Showa Kagaku K.K.,reagent grade 1) were weighed and blended so that a molar ratio (Ca/P)of calcium to phosphor was controlled to be 1.5, thereby to prepare amixed material.

20 g of this mixed material was put into a motor-driven mortar (ANM-1000type, mfd. by Aichi Denki K.K.) and mixed/milled for 22 hours under theconditions that the material was opened to atmosphere at room and arotation speed was set to 100 rpm, so that the soft-mechanochemicalcompositing reaction was advanced thereby to prepare a precursor.

An X-ray diffraction (XRD) profile of thus milled sample i.e.,β-tricalcium phosphate precursor produced by the soft-mechanochemicalcompositing reaction caused at mixing/milling operation is shown in FIG.7. On the other hand, the thermogravimetry-differential thermo analysismeasurement profile (TG-DTA graph) of the milled sample (precursor) isshown in FIG. 8. Further, in order to compare with the state shown inFIG.8, a TG-DTA graph of the mixed material before the milling operationis shown in FIG. 9.

As shown in FIGS. 7 and 8, both calcium hydroxide powder and calciumdihydrogenphosphate mono-hydrate powder as starting materials were notdetected in the sample after the milling treatment, so that it wasconfirmed that the soft-mechanochemical compositing reaction wascompletely finished.

Further, 1 gram of the above milled sample was put into an electricfurnace (hyper-speed, high-temperature muffle furnace, SF-17L type: mfd.by Shibata Kagaku Kiki Kogyo K.K.), then heated at a heating speed of10° C./min. in air atmosphere and subjected to a heat treatment at 600°C. for two hours or at 930° C. for one minute. The heat-treated samplewas analyzed by X-ray diffraction method.

As a result, it was confirmed that each of the substances produced bythe heat treatment was confirmed to be β-tricalcium phosphate crystalhaving a high degree of crystallization and a structural uniformity. Inthis connection, when the temperature of the heat treatment is set to beless than 600° C., the reaction was incompletely advanced, so that itwas found to be difficult to control the product qualities such aspurity or the like.

Using the same starting materials as in Example 4, the materials wereblended so that the molar ratios (Ca/P) of calcium to phosphor werechanged to 1.55 and 1.45 respectively, thereby to prepare materialmixtures. Each of the material mixture was subjected to the millingtreatment using the same mixing/milling device used in Example 4.

Thus obtained samples after the milling treatment were analyzed by X-raydiffraction method and differential thermal analysis. As a result, asthe same manner as in Example 4, it was confirmed that both calciumhydroxide powder and calcium dihydrogenphosphate mono-hydrate powder asstarting materials were not detected in the samples after the millingtreatment, so that it was also confirmed that the soft-mechanochemicalcompositing reaction was completely finished.

The products obtained by the above soft-mechanochemical compositingreaction were subjected to the heat treatment under the same conditionsas in Example 1. The heat-treated samples were analyzed by X-raydiffraction method.

As a result, it was confirmed that each of the substances produced bythe heat treatment was confirmed to be β-tricalcium phosphate crystalhaving a high degree of crystallization and a structural uniformity.

Purified water was added to each of the mixed/milled substances i.e.,β-tricalcium phosphate precursors obtained in the above Example 4thereby to prepare slurries each having a solid content of 15 wt%,respectively. Each of the slurries was left as it was for one weekunder a normal temperature and pressure, thereafter, dried at atemperature of 50° C. Thus obtained dried powder was analyzed by X-raydiffraction method. As a result, each of the precursors exhibited nochange from a state before the purified water was added, so that it wasconfirmed that each of the precursors had an excellent stability withrespect to water.

Further, each of the precursors obtained in Examples 4 were left as theywere for three months in a state where the precursors contacted toatmosphere under normal temperature and pressure, thereafter theresultant powders were analyzed by X-ray diffraction method. As aresult, each of the precursors exhibited no change from a state beforethe precursors was left as it was, so that it was also confirmed thateach of the precursors had an excellent stability with respect toatmosphere.

Further, when the mixing/milling process is terminated in a state beforethe soft-mechanochemical compositing reaction is completely finished inthe above Examples 4, even if the milled sample is one in which a smallamount of calcium hydroxide powder and calcium dihydrogenphosphatemono-hydrate powder as the starting materials is detected, β-tricalciumphosphate crystal particles having a high purity, high degree ofcrystallization and highly structural uniformity can be manufactured ifthe treating temperature in the subsequent heat treatment process issufficiently increased or the treating time is prolonged.

COMPARATIVE EXAMPLE 3

In accordance with a synthesizing method using the conventionalmechanochemical reaction, calcium carbonate powder (mfd. by Showa KagakuK.K., reagent grade 1) and calcium dihydrogenphosphate mono-hydrate(mfd. by Showa Kagaku K.K., reagent grade 1) were weighed and blended sothat a molar ratio (Ca/P) of calcium to phosphor was controlled to be1.5, thereby to prepare a mixed material.

Purified water was added to the mixed material so that a solid contentwas controlled to be 10 wt % thereby to prepare a material slurry. 20 gof this material slurry was put into a motor-driven mortar (ANM200 typeporcelain mortar mfd. by Nitto Kagaku K.K.). Then, the material slurrywas mixed and milled in a wet-process for 22 hours under the conditionsthat the slurry was opened to atmosphere of normal temperature, so thatthe mechanochemical reaction was advanced thereby to prepare a milledpowder. In this connection, to prevent the solid content in the slurryfrom increasing by evaporating water during the milling operation, themilling operation was conducted in such a manner that purified water wasappropriately added to the slurry on the way of the milling operation sothat the solid content of the slurry was maintained to a constant level.

Thus obtained milled powder was analyzed by X-ray diffraction method anddifferential thermal analysis. As a result it was confirmed that a largeamount of non-reacted substance was remained in the milled powder.Therefore, in the manufacturing method of Comparative Example 3 based onthe conventional mechanochemical reaction, although the millingoperation was conducted for a long time of 22 hours, the advancing speedof the mechanochemical reaction was remarkably lowered in comparisonwith those of EXAMPLE 4.

EXAMPLE 5

1 gram of the above precursor sample obtained in Example 1 was put intoan electric furnace, then heated at a heating speed of 10° C./min. andsubjected to a heat treatment at 930° C. for 10 minutes. Theheat-treated sample was analyzed by X-ray diffraction method. As aresult, it was confirmed that there could be obtained β-tricalciumphosphate crystal having a higher degree of crystallization and astructural uniformity than those in Example 1.

As is clear from the comparison with the treating conditions in Example1, it was confirmed that the longer retention time in the heat treatmentwill result in better crystallizing property for β-tricalcium phosphate.

EXAMPLE 6

1 gram of the above precursor sample obtained in Example 4 was put intoan electric furnace, then heated at a heating speed of 10°C./min. andsubjected to a heat treatment at 930° C. for 10 minutes. Theheat-treated sample was analyzed by X-ray diffraction method. As aresult, it was confirmed that there could be obtained β-tricalciumphosphate crystal having a higher degree of crystallization and astructural uniformity than those in Example 4.

As is clear from the comparison with the treating conditions in Example4, it was confirmed that if the retention time in the heat treatment wasprolonged, β-tricalcium phosphate having better crystallizing propertycould be obtained.

According to the method of manufacturing calcium phosphate powder ofExamples 1-6, calcium hydroxide powder and calcium dihydrogenphosphatepowder are mixed and milled, so that the soft-mechanochemical reactionis quickly advanced by catalytic actions of hydroxyl group and combinedwater, whereby β-tricalcium phosphate precursor can be formed in a shorttime in comparison with the conventional method. Further, fine crystalparticles of β-tricalcium phosphate can be effectively manufacturedthrough a heat treatment with a low treating temperature and a shorttime in comparison with the conventional method.

According to each of the above manufacturing methods of Examples, astrict control of pH value and temperature condition for the reactionsolution, which had been required in the conventional method asessential control, is not required, so that an operation control of themanufacturing equipment becomes extremely easy. In particular, themixing/milling operation is conducted in a dry-process, so that itbecomes possible to omit the drying process which had been required inthe conventional wet-type manufacturing method as an essential processbased on mechanochemical reaction in the conventional wet-type millingmethod (see, Japanese Patent Publication HEI3-69844). Therefore, anenergy efficiency (running cost) can be improved. In addition, itbecomes possible to omit a grind process for grinding again aggregationsof powder which is liable to occur in the drying process, so that themanufacturing process can be further simplified.

Further, according to each of the above manufacturing methods ofExamples, even if the outstanding method is compared with theconventional dry-process i.e. synthesizing method utilizinghigh-temperature solid phase reaction, fine βtricalcium phosphate powdercan be manufactured with a low cost in a short time through a simplemanufacturing facility.

EXAMPLE 7

Calcium hydroxide powder (mfd. by Kanto Kagaku K.K., reagent grade 1)and calcium dihydrogenphosphate mono-hydrate (mfd. by Showa Kagaku K.K.,reagent grade 1) were weighed and blended so that a molar ratio (Ca/P)of calcium to phosphor was controlled to be 1.5, thereby to prepare amixed material.

Purified water was added to the mixed material so that a solid contentwas controlled to be 40 wt % thereby to prepare a material slurry. 200 gof this material slurry was put into a casing 1 of a multi-ring mediatype ultrafine mill (MIC-O type mill mfd. by K.K. Nara Kikai Seisakusho,technical specification: zirconia ling) shown in FIGS. 1 and 2.

Under a state where a cooling water having a temperature of 15° C. wascirculated in a jacket 16 provided to an outer peripheral portion of thecasing 1 thereby to keep the temperature of the casing 1 to be aconstant value, a rotation speed of the main shaft 4 was set to 1200 rpmand wet-type mixing/milling operation for the mixed material slurry wascarried out for 300 minutes, so that the soft-mechanochemicalcompositing reaction was advanced thereby to prepare a precursor.

When the mixing/milling time had passed for 5 minutes, 10 minutes, 30minutes, 60 minutes and 300 minutes from the starting time of themixing/milling operation, slurry samples were sampled respectively, anddried at a temperature of 50° C. Thereafter, each of the dried sampleswere analyzed by X-ray diffraction method, and analyzed results areshown in FIG. 10. As is clear from the results shown in FIG. 10, bothcalcium hydroxide and calcium dihydrogenphosphate mono-hydrate asstarting materials were not detected at a stage when the mixing/millingtime was 60 minutes or more, so that it could be confirmed that thesoft-mechanochemical reaction was completely finished.

One gram of the dried slurry-sample of which mixing/milling time was 60minutes or more was subjected to a heat treatment in which the samplewas heated at a heating speed of 10° C./min. by means of an electricfurnace and maintained at 700° C. for one hour thereby to form calciumphosphate compound powder. Thus obtained powder sample analyzed by X-raydiffraction method. As a result, the sample was found to be β-tricalciumphosphate crystalline particles having a high degree of crystallizingand a structural uniformity.

When the manufacturing method of the above Example 7 is compared withthe manufacturing method utilizing a mechanochemical reaction to becaused in the conventional wet-type milling method, for example, themanufacturing method disclosed in Japanese Patent PublicationHEI3-69844, there is a remarkable difference as described hereunder.Namely, in the conventional manufacturing method, a maximum value of thesolid content of the material slurry is at most 15 wt %. In this case,the mixing/milling operation is required to be continued for a long timeof about 5-50 hours, so that the manufacturing cost of the product isdisadvantageously increased.

On the other hand, in the manufacturing method of Example of thisinvention, the solid content of the material slurry can be greatlyincreased up to 40 wt %, and the synthesizing reaction can be rapidlycompleted even if the mixing/milling time is set to a short time ofabout 60 minutes, so that it becomes possible to greatly increase asynthesizing amount of β-tricalcium phosphate per unit energy to be putinto the reaction system.

That is, according to the manufacturing method of Example of thisinvention, β-tricalcium phosphate precursor can be formed in a shortertime than that of the conventional wet-type synthesizing method, so thatβ-tricalcium phosphate powder can be efficiently mass-produced. Inparticular, since the solid content of the material slurry can be set toa high level of 40 wt % in comparison with the conventional method, itbecomes possible to remarkably shorten a drying time in the subsequentdrying process. In particular, when a multi-ring media type ultrafinemill capable of milling the material slurry having a high viscosity isused as a milling device and the mixing/milling operation iscontinuously performed, a production efficiency of β-tricalciumphosphate powder can be abruptly increased.

EXAMPLE 8

Calcium hydroxide powder (mfd. by Kanto Kagaku K.K., reagent grade 1)and calcium dihydrogenphosphate mono-hydrate (mfd. by Showa Kagaku K.K.,reagent grade 1) were weighed and blended so that a molar ratio (Ca/P)of calcium to phosphor was controlled to be 1.67, thereby to prepare amixed material. 50 g of this mixed material was mixed/milled under thesame operating conditions as in Example 1 using the ultrafine mill(FIGS. 1 and 2), so that a soft-mechanochemical compositing reaction wasadvanced thereby to prepare hydroxy calcium phosphate precursor. FIG. 11shows an X-ray diffraction profile (XRD profile) of thus preparedprecursor.

Next, one gram of the above precursor sample was subjected to a heattreatment in which the sample was heated in air-atmosphere at a heatingspeed of 10° C./min. by means of the electric furnace used in Example 1and maintained at 600° C. for one hour thereby to form a substance. FIG.12 shows an X-ray diffraction profile of the heat-treated sample.

As is clear from FIG. 12, the substance obtained by the heat treatmentwas found to be hydroxy calcium phosphate crystals having a high degreeof crystallizing and a structural uniformity.

Further, the materials used in above Example were blended so that themolar ratios (Ca/P) of calcium to phosphor were changed to 1.62 and 1.72respectively, thereby to prepare material mixtures. Each of the materialmixture was mixed and milled, thereafter subjected to the heat treatmentunder the same conditions as in the above Example. As a result, therecould be obtained hydroxy calcium phosphate crystals having a highdegree of crystallizing and a structural uniformity.

With respect to thus formed hydroxy calcium phosphate powder, SEManalysis and grain size analysis were conducted. As a result, each ofthe samples was found to consist of fine particles having an averagesize of about 500 nm.

EXAMPLE 9

Calcium hydroxide powder (mfd. by Kanto Kagaku K.K., reagent grade 1)and calcium dihydrogenphosphate mono-hydrate (mfd. by Showa Kagaku K.K.,reagent grade 1) were weighed and blended so that a molar ratio (Ca/P)of calcium to phosphor was controlled to be 1.67, thereby to prepare amixed material.

Purified water was added to the mixed material so that a solid contentwas controlled to be 40 wt % thereby to prepare a material slurry. 200 gof this material slurry was subjected to the wet-type mixing/millingoperation using the same mixing/milling device used in Example 7 underthe same operating conditions as in Example 7, so that thesoft-mechanochemical compositing reaction was advanced thereby toprepare hydroxy calcium phosphate precursor.

When the mixing/milling time had passed for 5 minutes, 15 minutes, 30minutes and 60 minutes respectively, slurry samples were sampled anddried at 50° C. FIG. 13 shows X-ray diffraction profiles of the driedsamples.

FIG. 13 shows a fact that the precursors obtained by the mixing/millingoperation for 30 minutes or more consist of a single phase of hydroxycalcium phosphate having a low crystallizing property.

One gram of the above dried sample obtained by the mixing/millingoperation for 30 minutes was subjected to a heat treatment in which thesample was heated in air-atmosphere at a heating speed of 10° C./min. bymeans of the electric furnace used in above Example and maintained at600° C. for one hour thereby to form a substance. Thus obtainedsubstance was analyzed by x-ray diffraction method. As a result, thesubstance was found to be hydroxy calcium phosphate crystals having ahigh degree of crystallizing and a structural uniformity.

By the way, in the manufacturing method according to each of Examples,X-ray diffraction profiles (FIGS. 3, 7, 10, 11 and 13) and TG-DTAprofiles (FIGS. 5 and 8) of the precursors to be formed after themixing/milling operation are greatly different to each other inaccordance with a kind of the milling devices such as multi-ring mediatype ultrafine mill and the motor-driven mortar or the like and theoperating conditions thereof However, the profiles show that when eachof the precursors was subjected to the heat treatment under suitableconditions, calcium phosphate powders such as β-tricalcium phosphatepowder hydroxy calcium phosphate powder or the like having a high purityand fine grain size can be obtained.

Accordingly, although any of milling devices such as ball mill, colloidmill, vibration mill or the like for general purpose other than themilling devices used in respective Examples can also used as the millingdevice (pulverizing device), in particular, when the multi-ring mediatype ultrafine mill shown in FIGS. 1 and 2 is used, thesoft-mechanochemical compositing reaction can be rapidly advanced evenif a material slurry having a high solid content and high viscosity isused.

In addition, when the heat-treating conditions such as such as treatingtemperature and treating time or the like for the calcium phosphatecompound precursors formed in each Examples are properly adjusted, thecrystallizing property of calcium phosphate fine particles such asβ-tricalcium phosphate fine particles and hydroxy calcium phosphate fineparticles or the like can be easily controlled.

INDUSTRIAL APPLICABILITY

As explained above, according to the method of manufacturing calciumphosphate powder of the present invention, calcium hydroxide powderhaving hydroxyl group or combined water exhibiting a large catalyticaction is mixed with calcium hydrogenphosphate powder and the mixture isthen milled, so that a soft-mechanochemical compositing reaction forforming calcium phosphate precursor is rapidly advanced whereby calciumphosphate compound powder can be efficiently manufactured.

In particular, when a multi-ring media type ultrafine mill comprising anumber of ring-shaped milling media is used as a milling device formilling the mixed material, a reaction activity of the mixed materialcan be remarkably increased, so that it becomes possible tosignificantly shorten a time required for the soft-mechanochemicalcompositing reaction.

What is claimed is:
 1. A method of manufacturing calcium phosphatepowder comprising the steps of: preparing a mixed material by mixingcalcium hydroxide (Ca(OH)₂) powder and calcium hydrogenphosphate powderso that a molar ratio (Ca/P) of calcium to phosphorus is set to a rangeof 1.45-1.72; conducting a mixing/milling treatment to said mixedmaterial to cause a soft-mechanochemical compositing reaction therebyforming a calcium phosphate precursor, wherein said mixture/millingtreatment is conducted by a dry-process; and conducting a heat treatmentto said calcium phosphate precursor at a temperature of 600° C. or morethereby forming calcium phosphate powder.
 2. A method of manufacturingcalcium phosphate powder according to claim 1, wherein said calciumhydrogenphosphate is at least one compound selected from the groupconsisting of calcium monohydrogenphosphate (CaHPO₄), calciummonohydrogenphosphate dihydrate (CaHPO₄.2H₂O), calciumdihydrogenphosphate (Ca(H₂PO₄)₂) and calcium dihydrogenphosphatemonohydrate (Ca(HPO₄)₂.H₂O).
 3. A method of manufacturing calciumphosphate powder according to claim 1, wherein said calcium phosphate isselected from the group consisting of β-tricalcium phosphate (TCP),calcium hydroxyphosphate (hydroxyapatite:HAp), and mixtures thereof. 4.A method of manufacturing calcium phosphate powder according to claim 1,wherein molar ratio (Ca/P) of calcium to phosphorus is set to a range of1.45-1.55, said calcium phosphate precursor is tricalcium phosphateprecursor, and said calcium phosphate is β-tricalcium phosphate (TCP).5. A method of manufacturing calcium phosphate powder according to claim1, wherein said molar ratio (Ca/P) of calcium to phosphorus is set to arange of 1.62-1.72, said calcium phosphate precursor is hydroxyapatite(HAp) precursor, and said calcium phosphate is calcium hydroxyphosphate.6. A method of manufacturing calcium phosphate powder according to claim1, wherein said mixing/milling treatment for said mixed material isperformed by means of a multi-ring media type ultrafine mill comprisinga plurality of ring-shaped pulverizing media.
 7. A method ofmanufacturing calcium phosphate powder according to claim 1, wherein acentrifugal effect (Z) imparted to the mixed material powder in themixing/milling treatment is at least 15.